Novel targets and inhibitors of the Mycobacterium tuberculosis cytochrome bd oxidase to foster anti-tuberculosis drug discovery

by Selleckchem | Oct 15 2023

Introduction: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the most devastating bacterial disease. Multidrug-resistant Mtb strains are spreading worldwide, underscoring the need for new anti-TB targets and inhibitors. The respiratory chain complexes, including the cytochrome bd oxidase (cyt-bd), have been identified as an attractive target for drug development. Recent novel structural and mechanistic insight as well as inhibitors of Mtb's cyt-bd brought this enzyme into the focus.

Areas covered: In this review, the authors describe conditions that stimulate the biogenesis of Mtb cyt-bd, its structural-, mechanistic-, and substrate-binding traits. They discuss the present Mtb cyt-bd inhibitors, novel targets within the enzyme and structure activity relationship features that are required for mycobacterial cyt-bd inhibition and augment their understanding on improving the potency of cyt-bd inhibitors.

Expert opinion: A deeper structure-mechanistic understanding of Mtb's cyt-bd is a prerequisite for in silico efforts to: (i) identify pathogen specific targets for the design of novel nontoxic hit molecules, forming the platform for the development of new leads, (ii) design mechanism of action studies, (iii) perform medicinal chemistry of existing inhibitors to improve their potency and pharmacokinetic/-dynamic properties. Phase studies with such optimized cyt-bd inhibitors in combination with anti-TB compounds targeting the oxidative phosphorylation pathway is recommended.

Comments:

Tuberculosis (TB) is a severe bacterial disease caused by Mycobacterium tuberculosis (Mtb) and continues to be a global health concern. The emergence and spread of multidrug-resistant Mtb strains have further emphasized the need for new targets and inhibitors to combat TB effectively. One promising target for drug development is the respiratory chain complexes, which include the cytochrome bd oxidase (cyt-bd) found in Mtb. Recent advancements in understanding the structure and function of Mtb cyt-bd, as well as the development of inhibitors, have highlighted its potential as a therapeutic target.

In this review, the authors provide an overview of the conditions that stimulate the production of Mtb cyt-bd and discuss its structural, mechanistic, and substrate-binding characteristics. They also examine the existing inhibitors of Mtb cyt-bd and explore novel targets within the enzyme. Furthermore, the authors delve into the structure-activity relationship features required for effective inhibition of mycobacterial cyt-bd, aiming to enhance the understanding of how to improve the potency of cyt-bd inhibitors.

The expert opinion expressed in the review emphasizes the importance of a comprehensive understanding of the structure and mechanism of Mtb cyt-bd. Such knowledge is crucial for conducting in silico studies to identify pathogen-specific targets and design new, non-toxic molecules as potential leads for drug development. It also enables the design of mechanism of action studies to further elucidate the functioning of cyt-bd. Additionally, the authors suggest that medicinal chemistry approaches can be employed to optimize existing inhibitors, improving their potency and pharmacokinetic/pharmacodynamic properties.

The review concludes by recommending phase studies involving optimized cyt-bd inhibitors in combination with anti-TB compounds targeting the oxidative phosphorylation pathway. This combinatorial approach has the potential to enhance the efficacy of TB treatment and overcome drug resistance. By exploring the potential of Mtb cyt-bd as a drug target, along with developing and optimizing inhibitors, researchers aim to contribute to the development of new and effective therapies against TB.